5-135033813-TGGCGGC-TGGC

Variant names:

• chr5-135033813-TGGC-T
• rs752690307
• NM_002653.5:c.66_68delGCC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_002653.5(PITX1):​c.66_68delGCC​(p.Pro23del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000478 in 1,401,790 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: PITX1 NM_002653.5 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.71
• Publications: 0 publications found

Genes affected

PITX1 (HGNC:9004): (paired like homeodomain 1) This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family are involved in organ development and left-right asymmetry. This protein acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin. [provided by RefSeq, Jul 2008]

PITX1-AS1 (HGNC:48332): (PITX1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_002653.5. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5	c.66_68delGCC	p.Pro23del	disruptive_inframe_deletion	Exon 1 of 3	ENST00000265340.12	NP_002644.4
PITX1	XM_047417318.1	c.168_170delGCC	p.Pro57del	disruptive_inframe_deletion	Exon 2 of 4		XP_047273274.1
PITX1-AS1	NR_161235.1	n.267+286_267+288delGGC		intron_variant	Intron 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX1	ENST00000265340.12	c.66_68delGCC	p.Pro23del	disruptive_inframe_deletion	Exon 1 of 3	1	NM_002653.5	ENSP00000265340.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.000329 AC: 52 AN: 158042 AF XY: 0.000358

Gnomad AFR exome AF: 0.000177

Gnomad AMR exome AF: 0.000423

Gnomad ASJ exome AF: 0.000258

Gnomad EAS exome AF: 0.000362

Gnomad FIN exome AF: 0.000331

Gnomad NFE exome AF: 0.000368

Gnomad OTH exome AF: 0.000750

GnomAD4 exome AF: 0.0000478 AC: 67 AN: 1401790 Hom.: 0 AF XY: 0.0000546 AC XY: 38 AN XY: 695550

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000340 AC: 1 AN: 29382

American (AMR) AF: 0.000385 AC: 15 AN: 39010

Ashkenazi Jewish (ASJ) AF: 0.0000809 AC: 2 AN: 24712

East Asian (EAS) AF: 0.000169 AC: 6 AN: 35578

South Asian (SAS) AF: 0.0000493 AC: 4 AN: 81062

European-Finnish (FIN) AF: 0.000207 AC: 8 AN: 38572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4062

European-Non Finnish (NFE) AF: 0.0000257 AC: 28 AN: 1091252

Other (OTH) AF: 0.0000516 AC: 3 AN: 58160

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.000329 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs752690307; hg19: chr5-134369503; COSMIC: COSV99530723; COSMIC: COSV99530723;